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New Nucleoside, Amdoxovir (DAPD), Potent When Combined With AZT
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
(Poster online at http://www.retroconference.org/2008/PDFs/794.pdf.)
Mark Mascolini
Amdoxovir (DAPD), a purine nucleoside analog, lowered viral loads up to 100-fold when combined with 200 or 300 mg of AZT twice daily for 10 days [1]. Viral loads dropped about half as far in people taking 500 mg of DAPD twice daily without AZT. The investigators saw no hematologic side effects in this short study of people with or without antiretroviral experience.
The rationale for developing a fixed-dose coformulation of amdoxovir and AZT rests on their complementary resistance profiles. Earlier work showed amdoxovir activity against M184V/I mutant virus (resistant to 3TC or emtricitabine) and certain mutants resistant to AZT or d4T [2]. K65R mutant virus, which has decreased susceptibility to amdoxovir [2], is incompatible with thymidine analog mutations provoked by AZT [3]. But some may question the strategy of combining a new nucleoside with AZT, a thymidine analog linked to lipoatrophy, anemia, and other side effects, and one no longer recommended as first-line therapy in most guidelines.
The double-blind, placebo-controlled trial involved 24 people not taking antiretrovirals who had a viral load above 5000 copies and got randomized as follows:
· Amdoxovir 500 mg twice daily or placebo
· AZT 200 mg twice daily plus amdoxovir or placebo
· AZT 300 mg twice daily plus amdoxovir or placebo
In active treatment arms CD4 count averages ranged from 336 to 472 and viral loads from 3.8 to 5.0 log (about 6300 to 100,000 copies). Only 3 study participants had a viral load above 100,000 copies. Eleven people had antiretroviral experience (5 of them in the AZT 300/amdoxovir arm). No one had nucleoside-related mutations when the trial began, though, oddly, everyone had a protease inhibitor-related mutation. The investigators did not list the PI mutations or explain this anomalous baseline trait.
At day 10 minimum and maximum viral load drops measured 1.8 and 2.2 log in the AZT 200/amdoxovir arm, 1.4 and 2.0 log in the AZT 300/amdoxovir arm, 0.3 and 2.4 in the amdoxovir-only arm, and lower in the AZT-only and placebo arms. Viral load changes did not differ significantly between the two AZT/amdoxovir arms.
Everyone taking amdoxovir with AZT had more than a 1-log (10-fold) dip in viral load; everyone taking amdoxovir with 200 mg of AZT and 5 of 6 people taking it with 300 mg of AZT had more than a 1.5-log drop. Six of 12 people taking amdoxovir with AZT reached a viral load below 400 copies by day 10. In contrast, only 1 of 6 people taking amdoxovir alone reached a sub-400 viral load, and only 2 of 6 taking the new nucleoside with AZT saw their viral load fall more than 10-fold. The investigators noted that CD4 changes through day 10 did not differ significantly between any groups, but they did not report absolute CD4 changes.
Eleven of 12 people combining amdoxovir with AZT had at least one clinical adverse event, including nausea in 6 of 12 and headache in 6 of 12. The researchers did not report changes in lab values, but they saw "no clinically relevant changes" in hemoglobin or mean corpuscular volume through 10 days and no changes from baseline in biochemistry, hematologic, or urinalysis values.
Mutations observed at study entry did not change, and no new mutations emerged during the trial.
Atlanta-based RFS Pharma, headed by nucleoside maven Raymond F. Schinazi, is developing amdoxovir.
References
1. Murphy R, Zala C, Ochoa C, et al. Pharmacokinetics and potent anti-HIV-1 activity of amdoxovir plus zidovudine in a randomized double-blind placebo-controlled study. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 794.
2. Mewshaw JP, Myrick FT, Wakefield DA, et al. Dioxolane guanosine, the active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of drug-resistant HIV-1 isolates from patients for whom standard nucleoside therapy fails. J Acquire Immune Defic Syndr. 2002;29:11-20.
3. Parikh UM, Zelina S, Sluis-Cremer N, Mellors JW. Molecular mechanisms of bidirectional antagonism between K65R and thymidine analog mutations in HIV-1 reverse transcriptase. AIDS. 2007;21:1405-1414.
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